DFF40 deficiency in cancerous T cells is implicated in chemotherapy drug sensitivity and resistance through the regulation of the apoptotic pathway

Kulbay, Merve; Johnson, Bruno; Fiola, Sophie; Diaz, Roberto J.; Bernier, Jacques

doi:10.1016/j.bcp.2021.114801

Cited by 4 publications

(1 citation statement)

References 84 publications

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“…Smac improves caspase activation by combining inhibitors of apoptosis proteins. Ultimately, Caspase 3-mediated cleavage of DFF45 releases DFF40, leading to chromatin condensation and triggering cell death ( 38 ). Based on these findings, we inferred that the mitochondria-dependent apoptotic pathway was activated by HRS in HCT-116 cells.…”

Section: Discussionmentioning

confidence: 99%

Hydroxy-γ-sanshool from Zanthoxylum bungeanum (prickly ash) induces apoptosis of human colorectal cancer cell by activating P53 and Caspase 8

et al. 2022

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Sanshools, long-chain polyunsaturated amides in Zanthoxylum bungeanum (prickly ash), have important bioactivity. The objective was to assess inhibitory effects and molecular mechanisms of sanshools isolated from supercritical fluid (SCF) extract on human colon adenocarcinoma cells (HCT-116) cultured in vitro. Cells were exposed to various concentrations (0, 50, 90, or 130 μM) of sanshools for 24 or 48 h, with assessment of apoptosis and cell cycle arrest as well as regulatory gene and protein expression associated with apoptosis and the cell cycle. Sanshools profoundly inhibited growth of HCT-116 cells, with hydroxy-γ-sanshool (HRS) being the optimal active component (IC50 = 88.01 μM) inhibiting cell proliferation and having no cytotoxic effect to normal cells (IC50 = 481.52 μM) by CCK-8 assay. In HCT-116 cells, HRS inhibited cell growth, induced morphological distortion, and arrested the cell cycle at G1 phase (50.31 ± 4.13% vs. 72.16 ± 8.14% in Control and 130 μM HRS, respectively), and also caused programmed cell death in a dose-dependent manner. The percentage of apoptotic cells were remarkably increased after treated with HRS (6.2, 11.9, 19.8, and 30.7% for 0, 50, 90, and 130 μM, respectively). Moreover, in HCT-116 cells, HRS significantly inhibited mRNA and protein levels of Cyclin D1, CDK4, PCNA, and increased mRNA and protein levels of P21, P53, Fas, and Caspase 8. Furthermore, inhibitors of P53 and Caspase 8 proteins significantly mitigated the HRS-induced cell cycle arrest and apoptosis. In conclusion, our study provides evidence that HRS induced human colorectal cancer cell apoptosis by up-regulating P53 and Caspase 8.

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Section: Discussionmentioning

confidence: 99%

Hydroxy-γ-sanshool from Zanthoxylum bungeanum (prickly ash) induces apoptosis of human colorectal cancer cell by activating P53 and Caspase 8

et al. 2022

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The Role of Curcumin as an Anti-Aging Compound

Karthika

Akter

Rahman

et al. 2023

Emerging Anti-Aging Strategies

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Energetic metabolic reprogramming in Jurkat DFF40-deficient cancer cells

et al. 2022

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DNA fragmentation factor 40 (DFF40), or the caspase-activated DNase (CAD), is an endonuclease specific for double-stranded DNA. Alterations in its function and expression have been linked to apoptosis resistance, a mechanism likely used by cancer cells.Although, how the DFF40-related apoptosis resistance pathway occurs remains unclear.Here we sought to determine if DFF40 expression could be linked to cell metabolism through the regulation of mitochondrial integrity and function. We demonstrated that DFF40 deficient cells are more resistant to staurosporine (STS) and tributyltin (TBT)induced apoptosis, and express higher levels of Mcl-1 at basal state. Treatment with TBT induces higher Bcl-2 and caspase-9 mRNA transcripts in DFF40 KO Jurkat cells, as well as enhanced Bcl-2 phosphorylation. A loss of DFF40 expression induces a higher mitochondrial mass, mtDNA copy number, mitochondrial membrane potential and glycolysis rates in resting T cells. DFF40 deficient cells exhibit the Warburg effect phenotype, where they rely significantly more on glycolysis and have a higher proliferative state, demonstrated by a higher Ki-67 transcription factor expression and AKT phosphorylation. Finally, we demonstrated with cell fractioning that DFF40 can translocate to the mitochondria following apoptosis induction. Our study reveals that DFF40 may act as a regulator of mitochondria during cell death, and its loss could compromise mitochondrial integrity and cause an energetic reprogramming in pathologies such as cancer.

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DFF40 deficiency in cancerous T cells is implicated in chemotherapy drug sensitivity and resistance through the regulation of the apoptotic pathway

Cited by 4 publications

References 84 publications

Hydroxy-γ-sanshool from Zanthoxylum bungeanum (prickly ash) induces apoptosis of human colorectal cancer cell by activating P53 and Caspase 8

Hydroxy-γ-sanshool from Zanthoxylum bungeanum (prickly ash) induces apoptosis of human colorectal cancer cell by activating P53 and Caspase 8

The Role of Curcumin as an Anti-Aging Compound

Energetic metabolic reprogramming in Jurkat DFF40-deficient cancer cells

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